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DeepPET Uses Artificial Intelligence to Generate Images of the Body’s Internal Activities

Source: Memorial Sloan Kettering - On Cancer
Date: 04/19/2019
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Recently, the first-ever image of a black hole was splashed across front pages and filled up news feeds around the world. The image was made in part thanks to tremendous computing power that analyzed millions of gigabytes of data that had been collected from space.

Research that uses computer algorithms to create pictures from massive volumes of data is also going on at Memorial Sloan Kettering. Instead of probing the outer limits of the universe, this work seeks new ways to see what’s going on inside our bodies.

In a paper published in the May 2019 issue of Medical Image Analysis, MSK investigators led by medical physics researcher Ida Häggström report the details of a new method they developed for PET imaging. The system generates images more than 100 times faster than conventional techniques. The images are also of higher quality.

“Using deep learning, we trained our convolutional neural network to transform raw PET data into images,” Dr. Häggström says. “No one has done PET imaging in this way before.” Convolutional neural networks are computer systems that try to mimic how people see and learn what the important shapes and features in images are.

Deep learning is a type of artificial intelligence. In this technique, a computer system learns to recognize features in the training data and apply that knowledge to new, unseen data. This allows the system to solve tasks, such as classifying cancerous lesions, predicting treatment outcomes, or interpreting medical charts. The MSK researchers, including medical physicist Ross Schmidtlein and data scientist Thomas Fuchs, the study’s senior author, named their new technique DeepPET.

Peering into the Body’s Inner Workings

PET, short for positron-emission tomography, is one of several imaging technologies that have changed the diagnosis and treatment of cancer, as well as other diseases, over the past few decades. Other imaging technologies, such as CT and MRI, generate pictures of anatomical structures in the body. PET, on the other hand, allows doctors to see functional activity in cells.

The ability to see this activity is especially important for studying tumors, which tend to have dynamic metabolisms. PET uses biologically active molecules called tracers that can be detected by the PET scanner. Depending on which tracers are used, PET can image the uptake of glucose or cell growth in tissues, among other phenomena. Revealing this activity can help doctors distinguish between a rapidly growing tumor and a benign mass of cells.

PET is often used along with CT or MRI. The combination provides comprehensive information about a tumor’s location as well as its metabolic activity. Dr. Häggström says that if DeepPET can be developed for clinical use, it also could be combined with these other methods 

Improving on an Important Technique

There are drawbacks to PET as it’s currently performed. Processing the data and creating images can take a long time. Additionally, the images are not always clear. The researchers wanted to look for a better approach.

The team began by training the computer network using large amounts of PET data, along with the associated images. “We wanted the computer to learn how to use data to construct an image,” Dr. Häggström notes. The training used simulated scans of data that looked like images that may have come from a human body but were artificial.

The images from the new system were not only generated much faster than with current PET technologies but they were clearer as well.

Conventionally, PET images are generated through a repeating process where the current image estimate is gradually updated to match the measured data. In DeepPET, where the system has learned the PET scanner’s physical and statistical characteristics as well as how typical PET images look, no repeats are required. The image is generated by a single, fast computation.

Dr. Häggström’s team is currently getting the system ready for clinical testing. She notes that MSK is the ideal place to do this kind of research. “MSK has clinical data that we can use to test this system. We also have expert radiologists who can look at these images and interpret what they mean for a diagnosis.

“By combining that expertise with the state-of-the-art computational resources that are available here, we have a great opportunity to have a direct clinical impact,” she adds. “The gain we’ve seen in reconstruction speed and image quality should lead to more efficient image evaluation and more reliable diagnoses and treatment decisions, ultimately leading to improved care for our patients.”

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One Patient’s Exceptional Response Leads to a Surprising Discovery about Immunotherapy

Source: Memorial Sloan Kettering - On Cancer
Date: 04/30/2019
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Findings from a single person with cancer can kick-start a major scientific breakthrough. When one person benefits from treatment in an uncommon way, doctors call it an exceptional response. In this era of personalized medicine, exceptional responses offer clues about how a drug or class of drugs works.

In a study published online on April 22 by Nature Medicine, a group of Memorial Sloan Kettering doctors and scientists describes one such exceptional response. The research suggests that in some cancers, genetic changes called gene fusions can occasionally send signals that the immune system can recognize. These signals can boost the effectiveness of immunotherapy drugs called checkpoint inhibitors. Checkpoint inhibitors take the brakes off the immune system and allow it to attack tumor cells.

“This is a great reminder that despite what we know about how immunotherapy and other cancer drugs work, we’re far from understanding all the rules,” says physician-scientist Timothy Chan, one of the paper’s two senior authors.

“What we’ve learned from this one patient has opened a new door,” adds surgeon-scientist Luc Morris, the paper’s other senior author. “Our findings suggest a new way that the immune system can recognize and attack certain types of tumors. But we’re really just at the beginning of knowing how to apply this discovery and target these alterations. We are working on the next steps in the laboratory.”

An Unexpected Outcome

The exceptional response described in the paper was in a teenage girl with a head and neck cancer that had spread to her lungs. She initially saw Dr. Morris, a head and neck cancer surgeon, who began tests to genetically profile the tumor, saving samples in the hopes of learning more about her cancer in the future. She was then treated by MSK pediatric oncologist Leonard Wexler with chemotherapy, which kept the disease stable. When the cancer started growing again, Dr. Wexler decided to try the immunotherapy drug pembrolizumab (Keytruda®).

“Further chemotherapy was unappealing because of the side effects and the limited chance that it would be effective,” Dr. Wexler says. “We also knew that the tumor had some unusual features for a head and neck cancer. We decided to think outside the box about how to treat the patient.”

Only about 12 to 15% of head and neck cancers respond to drugs like pembrolizumab. An initial analysis of this patient’s tumor suggested that she was not likely to be one of them.

There were two reasons for this belief. For one, her tumor had very few mutations. It’s known that the more mutations a tumor has, the more likely it is to respond to checkpoint inhibitors. That’s because having a lot of mutations means a tumor is more likely to produce proteins called neoantigens, which the immune system recognizes as foreign. This discovery was first reported in 2014 by Dr. Chan and his colleagues.

Additionally, her tumor was “cold,” meaning it had little immune activity around the tumor cells. By contrast, tumors described as “hot” — with many immune cells interspersed among the tumor cells — are more susceptible to checkpoint inhibitors. Immune cells can more easily find and attack a cancer when they’re already in the vicinity.

Despite these factors, the girl’s cancer had begun to shrink within five months. After three more months, it had completely disappeared. The MSK team decided to take a deeper dive, studying the tumor in greater detail to figure out why.

A Focus on Neoantigens

After sequencing the entire genome of the patient’s tumor, the MSK team discovered it had a kind of alteration called a gene fusion. Gene fusions occur when a gene from one chromosome breaks off during cell division and attaches to a gene on another chromosome. This new combined gene can make a protein that drives cancer growth.

“The fusion that this patient had was totally unheard of, something that has not been seen before,” Dr. Morris says. “But this gene fusion is probably what caused her cancer.”

The researchers discovered that the protein created by the gene was a neoantigen. “Neoantigens are seen as foreign by the immune system. They’re something that doesn’t belong in the body,” says Dr. Chan, who is Director of MSK’s Immunogenomics and Precision Oncology Platform. “In this case, the neoantigen resulting from the gene fusion made the patient’s cancer susceptible to immunotherapy.”

Looking for Potential Benefit in More Cancer Types

Although this patient’s particular gene fusion was rare, other fusions are more common in certain cancer types. The investigators analyzed tumors from other people treated at MSK for a type of head and neck cancer with common fusions. They found that immune cells in these people were able to recognize tumor cells with these gene fusions.

“One of the things that our team is doing now is systematically going through every single gene fusion across human cancers and predicting which ones may result in neoantigens that can be seen by the immune system,” Dr. Chan says. “We expect these findings are going to apply broadly to many different types of cancer.”

The original patient completed treatment with pembrolizumab and has remained free of cancer. It has been more than 30 months from when she started immunotherapy.

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Why Do Germs Become Resistant to Antibiotics? An MSK Program Is Focused on Avoiding this Problem

Source: Memorial Sloan Kettering - On Cancer
Date: 05/22/2019
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The rapid emergence of drug-resistant microorganisms is “a global crisis that threatens a century of progress in health and achievement,” according to a recent report from the World Health Organization. Increasingly, experts have been sounding the alarm about the evolution of drug resistance. As a result, many common infectious diseases may become untreatable.

The best way to prevent microorganisms from developing resistance is ensuring that antimicrobial drugs are used properly. Memorial Sloan Kettering was one of the first hospitals in New York City to recognize and address this problem. In 2001, MSK established a program to oversee the use of antibiotics and other antimicrobial drugs. It has since served as a model for other cancer centers.

In an interview, Susan Seo, an infectious disease doctor who leads MSK’s Antibiotic Management Program, talks about how MSK is leading the way in ensuring that these drugs are used responsibly.

Why is a cancer hospital focused on antibiotic use?

Infections are a major complication of cancer treatment. We know that preventing and treating them improves patients’ overall health and outcomes.

People with cancer may be more prone to infections because of the underlying disease itself. They may also have weakened immune systems as a result of the therapy they’re receiving to treat the cancer. Subsequently, most people with cancer receive antibiotics at some point during their treatment.

Why is it important to ensure that antibiotics are used properly?

If people take antibiotics when they don’t need them, they may end up with bacteria that can resist those antibiotics. People who have infections due to antibiotic-resistant bacteria can have longer and more serious infections. They may have limited treatment options. And they can die from antibiotic-resistant infections. In addition, people who take a lot of antibiotics can develop side effects. These might include a rash or antibiotic-related diarrhea caused by the bacterium Clostridium difficile. So it’s important that antibiotics are prescribed to people only when they are truly needed.

I think of antibiotics as a precious resource. If we run out of effective antibiotics to treat or prevent infections for people with cancer, then giving chemotherapy or doing surgery becomes very high risk.

What is the role of the Antibiotic Management Program at MSK?

Antibiotic stewardship is a commitment to using antibiotics optimally and safely. My team includes infectious disease–trained clinical pharmacists. Together, we assist doctors and nurses at our hospital in ensuring that antibiotics are prescribed with the appropriate drug, dose, and duration. This allows the drugs to wipe out infections that have been diagnosed and prevent others from occurring. We want to ensure that antibiotics are stopped if there is no evidence of infection.

Members of the program are engaged in teaching our colleagues about antibiotic stewardship because it’s everybody’s responsibility to use antibiotics wisely. In this way, we can preserve them not just for today but for all the generations that come after us.

Can you give an example of how this program has made a difference in patient care?

The problem of antibiotic resistance is due to misuse or overuse of antibiotics. A common example is taking an antibiotic for a viral infection, such as the common cold.  

We recently did a collaborative study with our colleagues on the Lymphoma Service. We wanted to see how many of the people who had cold symptoms were getting antibiotics.

We then developed guidelines that describe the features of common upper respiratory tract infections, the diagnostic workup, and how to manage them. We used the Centers for Disease Control and Prevention’s recommendations for treating upper respiratory tract infections.

We educated doctors and nurses about this issue. The guidelines were posted in the workroom pods. We then looked to see if this made a difference. Happily, we found that the rate of antibiotic prescriptions for upper respiratory tract infections dropped. We recently presented this work at MSK’s Quality Improvement Fair.

My team is now pondering how to build on this work. One focus is keeping this effort going in lymphoma care. We are also thinking about adapting this approach for other outpatient clinics at MSK.

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What Can Be Learned from a Negative Clinical Trial? Findings from a Sarcoma Study at ASCO 2019

Source: Memorial Sloan Kettering - On Cancer
Date: 06/02/2019
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At this year’s American Society of Clinical Oncology (ASCO) annual meeting, researchers from around the world have gathered to learn about the latest advances in cancer treatment. Much of the research being discussed highlights meaningful improvements in cancer care. At least one study, however, is attracting a lot of attention despite disappointing results.

That study, for advanced soft-tissue sarcoma, was called the ANNOUNCE trial. ANNOUNCE was a randomized study that compared a combination treatment of the chemotherapy drug doxorubicin and the targeted drug olaratumab (Lartruvo®) to doxorubicin on its own. The trial found that adding olaratumab to chemotherapy did not increase survival.

Based on an earlier report from this phase III study, Eli Lilly, the company that makes olaratumab, announced in April 2019 that it is withdrawing the drug from the market.

Memorial Sloan Kettering sarcoma expert William Tap led the ANNOUNCE trial as well as earlier studies on olaratumab. In an interview, he talked about why the findings from the study were disappointing and what’s next for sarcoma treatment.

What was MSK’s role in the research that led to olaratumab’s approval?

We led the phase II trial, which was published in June 2016. That study included 133 people with many subtypes of sarcoma. The participants were randomized to receive either olaratumab and doxorubicin or doxorubicin alone. All of the participants had advanced disease that had spread beyond the original tumor.

The average survival of people who got the combination was 26.5 months, compared with 14.7 months for those who got standard treatment, which was doxorubicin alone. Sarcoma is very hard to treat, and there are few good options once it has spread and can no longer be eliminated with surgery. The findings that olaratumab extended life for nearly a year were remarkable. We felt very hopeful based on those results.

The drug was given accelerated approval from the US Food and Drug Administration in October 2016 based on that study’s impressive results and the unmet need for sarcoma treatments. It also received conditional approval in Europe.

What are you presenting at ASCO this year?

These are the results from the follow-up phase III trial. The FDA required this study to confirm the benefit seen in the earlier trial. Unlike the earlier study, this one unfortunately was negative. Overall survival, which is how long someone lives after starting treatment, was not statistically higher in the group that got olaratumab.

Nearly three-quarters of new cancer drugs fail in phase III trials. But it’s much more unusual for a drug to fail a phase III trial after receiving accelerated or conditional approval.

Those of us in the sarcoma research community are still trying to understand why we saw such different results between the two trials. There are a lot of possibilities. It may be differences in the way the two studies were designed. It could also be the types of patients who were enrolled in the studies and the specific subtypes of disease that they had.

One thing that’s important to mention is that olaratumab didn’t add any serious side effects, compared with chemotherapy alone.

What did you learn from this study?

Sarcoma is a rare disease, and anytime you’re able to collect this much data on a rare disease, it’s going to be useful. There are not many large, multicenter studies on sarcoma. What we’ve learned will be helpful in our overall understanding of this disease. It will also help us design other clinical trials in the future.

One remarkable outcome was that the survival in the control group, those who got only doxorubicin, was higher than what we’ve ever seen in any other phase III clinical trial. Many of these patients did quite well, even without receiving any benefit from olaratumab. This is the third time in the past five years where a negative phase III study has shown such measurable improvements in the control arm compared with historical outcomes.

There are likely several reasons that these patients did so much better than expected. We think it’s because of overall advances in the way this disease is treated — including progress in surgery, radiation, and supportive care. There have also been improvements in treating particular subtypes as we increase our understanding of what drives them.

I can’t overstate the exceptional effort from everyone who worked on the phase II and phase III trials. For this trial, we were able to enroll and care for 509 participants at 110 hospitals in 25 countries.

Eli Lilly announced in April that it was removing olaratumab from the market. What will happen to people who are already taking the drug?

At MSK, we are not recommending that anyone start taking the drug. For those who are already taking it, we are phasing out that treatment.

There are some patients who perceive that the drug is helping them. It’s possible it is, since sarcoma is a heterogeneous disease and not all tumors behave the same way. But we don’t yet have enough insight to know which subtypes or disease characteristics may respond to olaratumab.

The drug company is working with people who have been taking the drug and, in some circumstances, will continue to provide it. The details are still being determined.

What else should people know about this research?

This shows the complexity of researching a disease like sarcoma, which is actually not one cancer but about 50 or 60 diseases. Each sarcoma has its own biology. It’s important for us to continue studying all these different types so that we can develop more-effective, personalized therapies.

I’m worried that what happened with olaratumab will negatively impact the development of other sarcoma drugs. Because sarcoma is less common than many other cancers, it’s already hard to get funding for it. Treatment is getting better, as our results for patients in the control group showed, but there is still a great need to find better drugs.

This is just the nature of science sometimes. There is no reason to give up hope.

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Ro Versus Musashi: How One Molecule Can Turn Cancer Cells Back to Normal

Source: Memorial Sloan Kettering - On Cancer
Date: 06/19/2019
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Since 2012, Memorial Sloan Kettering cancer biologist Michael Kharas has focused on studying a family of proteins called Musashi. These proteins play a role in acute myeloid leukemia (AML) as well as in many solid tumors, including colorectal, breast, lung, and pancreatic cancers. Musashi proteins function by binding to messenger RNAs. These molecules serve as a template for making proteins.

On June 19, 2019, in Nature Communications, Dr. Kharas’s team reported that they have identified a molecule that appears to block the function of Musashi-2. This protein plays a role in making cancer grow and spread. The compound appears to eliminate tumor cells in human cancer cell lines and in mice.

“This research provides a strategy for how to develop inhibitors for RNA-binding proteins,” says Dr. Kharas, who is in the Sloan Kettering Institute’s Molecular Pharmacology Program. “Historically, it’s been difficult to develop inhibitors to proteins that bind to RNA because of their challenging structural properties.

“We don’t think this particular compound will ultimately make it into clinical trials,” he adds, “but we now have a road map to guide us in future drug development.”

Turning Cancer Cells Back to Normal

This latest work builds on earlier research from Dr. Kharas’s lab, in which the investigators started with more than 150,000 molecules that could potentially block Musashi-2. They then developed a number of tests that could rapidly look for effective molecules in an automated way. Eventually, they settled on a molecule called Ro 08-2750, or just Ro for short.

In the current study, the team used structural biology to look at where Ro binds to Musashi-2. “Based on this research, we have an idea of where to start in designing additional molecules that could be used as drugs,” Dr. Kharas says. “We know the binding region and how the drug fits.”

Researchers know that Musashi-2 plays a role in how aggressive cancer is. The protein is present in more than 70% of people with AML. Solid tumors that contain a high level of the protein are more likely to grow, spread, and resist treatment. It appears that Musashi-2 allows cancer cells to continue growing and resist signals to die.

“Musashi-2 is required for cancer stem cells to survive,” Dr. Kharas explains. Cancer stem cells are cancer cells that have the ability to give rise to all types of cells within a tumor. “When Ro was added to AML cells in a dish, the cells became normal. They stopped growing and died.” The same effects were observed in mice that had AML

A Cooperative Effort among Several Labs

This research was possible due to collaboration among many different experts at MSK. The project was overseen by Gerard Minuesa, a postdoctoral researcher in Dr. Kharas’s lab.

SKI computational chemist John Chodera, SKI structural biologist Dinshaw Patel, and Yehuda Goldgur, Head of MSK’s X-Ray Crystallography Core Facility, helped determine the structure of the Musashi-2 protein and how Ro binds to it. SKI computational biologist Christina Leslie helped with the gene expression data generated from this research.

“Thanks to this study, we’ve shown that it’s possible to develop drugs for these difficult targets,” Dr. Kharas concludes. “It provides a path forward for future work, so we can eventually develop drugs that can be tested in clinical trials in people with cancer.”

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Research Clarifies How IDH Mutations Cause Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 07/01/2019
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A family of genes called IDH are associated with cancer. These genes make enzymes called isocitrate dehydrogenases. The enzymes help break down nutrients and generate energy for cells. Mutations in IDH genes prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become.

When cells can’t differentiate properly, they may begin to grow out of control. Scientists are still learning about what controls this process.

Now a team of researchers working in the lab of Memorial Sloan Kettering President and CEO Craig Thompson have made discoveries about how this malfunction occurs, at least in test tubes. Although the work is still in an early stage, they hope their findings will eventually contribute to new approaches for developing cancer drugs.

“Although IDH mutations are not very common overall, there are some diseases where these genetic changes contribute to a significant portion of cases,” says Juan-Manuel Schvartzman, a postdoctoral fellow in the Thompson lab, an instructor in the Gastrointestinal Oncology Service, and the first author of a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). “For these subtypes of cancer, better targeted therapies are needed.”

IDH mutations are found in about one-quarter of people with acute myeloid leukemia (AML), the most common type of leukemia in adults. They may also be found in a type of bile duct cancer called cholangiocarcinoma, a bone cancer called chondrosarcoma, low-grade glioma, and some kinds of lymphoma. The mutations occur much less frequently in more common cancers, such as colon cancer, breast cancer, and lung cancer.

Deciphering Underlying Changes

To learn more about how IDH mutations block differentiation, the investigators studied them in the context of a well-characterized model: cells called fibroblasts that can be coaxed to become muscle cells. By figuring out how the mutations prevent muscle cells from forming properly, the team aimed to get at the underlying defects in cells that these mutations cause.

Earlier research showed that IDH mutations influence cells through epigenetic changes. Epigenetics involves changes in gene expression that do not cause changes in the DNA sequence. Many of these have to do with the way DNA is packaged in the nucleus of a cell. The strands are wrapped around spool-like proteins called histones. Small chemical groups attached to DNA and histones — including fragments called methyl groups — can affect how DNA is spooled. Ultimately, this can influence how and when genes get made into proteins.

Specifically, IDH mutations lead to the formation of a molecule called 2-hydroxyglutarate (2HG). This molecule, in turn, can block the removal of methyl groups.

In the PNAS paper, the investigators dove deeper into the specific epigenetic changes caused by IDH mutations. “What we found was that they didn’t have much to do with DNA methylation, which is what we previously thought,” Dr. Schvartzman says. “Instead, they were related to methylation on histones.”

This change affects how the DNA strands are wrapped around histones. When they are tightly wrapped, it can prevent certain regions of DNA from being accessible. This can affect which genes get made into proteins.

Expanding the Development of Drugs

There already are drugs that are approved to work in AML caused by IDH mutations. Ivosidenib (Tibsovo®) targets IDH1, and enasidenib (Idhifa®) targets IDH2. Both of these drugs prod cancer cells into differentiating normally. But investigators say that there are many more avenues to be explored for new drugs that work against IDH-mutant cancers.

“I’m very interested in looking not just at tumors that are IDH mutant but more broadly at how these cellular changes affect the ability of those cells to differentiate,” Dr. Schvartzman says. “In addition to the buildup of 2HG, there are other changes in the cell that may prevent methyl groups from being removed from histones. We want to study those as well.

“It’s a little early to talk about how this could be applied to new drugs,” he concludes. “But one thing that’s exciting is the ability to understand more about how cells are wired and how different cellular changes affect levels of methylation. There are many enzymes we can start to explore that could be interesting for new cancer drugs.”

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Scientists Develop a Tool to Watch a Single Gene Being Transcribed in a Living Cell

Source: Memorial Sloan Kettering - On Cancer
Date: 07/05/2020
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A picture is worth a thousand words, or so the saying goes. But it can be quite a challenge to capture a picture of something that’s so tiny it’s on the scale of individual molecules.

The field of structural biology is dedicated to constructing images of very, very small things. But most of the techniques used by structural biologists to take these pictures require that the molecules are frozen in one position. This makes it difficult to watch the dynamic, shifting processes that are essential to life.

For the first time, researchers from the Sloan Kettering Institute have found a way to peer inside living cells and observe gene transcription. This is the process by which DNA is copied into messenger RNA (mRNA), which then specifies how a protein is made.

“Gene transcription is one of the most fundamental processes in all of biology,” says SKI structural biologist Alexandros Pertsinidis, senior author of the study, which was published in Cell. “We know that it’s highly regulated and uses complicated molecular machinery. Being able to watch this process as it happens is an important step forward in understanding what goes on inside cells.”

Following the Recipe

If you think of the genetic code as a universal cookbook, containing all of the instructions needed to make every part of a living organism, you can think of the various cell types as different restaurants, Dr. Pertsinidis explains. “French restaurants follow French recipes to make French dishes, and Italian restaurants follow Italian recipes to make Italian dishes,” he says. “In the same way, brain cells make the proteins that brain cells need to function, and liver cells make the proteins for liver function.”

A family of enzymes called RNA polymerases and a large set of factors that are associated with them regulate the transcription of individual genes and control the characteristics that cells exhibit. “The interplay between RNA polymerases and regulatory factors helps determine which genes are turned on and off in specific cells,” he says. “They also control how cells respond to outside signals, which can influence their activities.”

Until now, the function of RNA polymerases and associated regulatory factors has been studied indirectly, through biochemical reactions: Cells are broken open in a test tube and purified into individual parts. By adding or removing components and measuring the outcomes, scientists have been able to figure out certain molecular activities. How the machine as a whole works inside cells, however, has remained obscure.

“For 50 years, hundreds of researchers all over the world have studied these reactions,” Dr. Pertsinidis says. “But the problem has been that nobody has been able to directly observe how gene transcription happens inside a live cell.”

Zooming In on a Single Gene

In the study, the investigators used a highly specialized optical microscope to look at the activity of one RNA polymerase, called RNA polymerase II, as it interacted with genes and synthesized mRNA. The new method, developed by Dr. Pertsinidis’s lab, is called single-molecule nanoscopy.

To be able to look at the individual parts of cells, researchers label molecules with a fluorescent tag that makes them glow under the microscope. “But a cell is very crowded, and there are many reactions happening at the same time,” Dr. Pertsinidis says. “If you label all the polymerases in a cell, the whole nucleus is just a big glow.

“What’s new about this technology is the ultrasensitive, integrated system that lets us zoom in on a single tagged gene even when the cell nucleus is moving around and the specific chromosomal location is jiggling due to random microscopic motion,” he says. “At the same time, the system suppresses the signals from the other reactions that are happening, casting them into the background. This enables us to extract the signal for only the gene of interest and zoom in on it.”

The organization and dynamics of RNA polymerase II in the nucleus have been a topic of intense study over the past few decades. “Here, we directly observed the activity of this molecule and how it functions in the nucleus of live cells,” Dr. Pertsinidis says. “Being able to see how it interacts with other regulatory factors has unveiled the intricate hierarchies and interdependencies of these various factors. These insights enable us to reach a more detailed and comprehensive picture of transcription in live cells.”

Expanding to Other Cellular Processes

The researchers hope that their tool will be widely used to study complicated reactions inside living cells.

“There are enough details in our paper that other labs will be able to pick up and implement the technology,” Dr. Pertsinidis says. “We also have labs both inside and outside MSK that are interested in collaborating with us on specific projects.”

He adds that although he is focused on understanding gene transcription, the tools his team has developed could be used to study the details of other vital biological processes, such as DNA repair and protein synthesis.

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FDA Approves Pexidartinib, a Targeted Therapy for a Tumor of the Joints

Source: Memorial Sloan Kettering - On Cancer
Date: 08/05/2019
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On August 2, the US Food and Drug Administration announced that it had approved pexidartinib (TuralioTM) for certain people with tenosynovial giant cell tumor (TGCT). It is the first drug approved specifically to treat this rare tumor of the joints.

Memorial Sloan Kettering medical oncologist and sarcoma expert William Tap led the clinical trials for this drug. The results of a phase III study were published in June 2019 in The Lancet.

“For the right patient, this is a drug that can really help,” Dr. Tap says. “However, because of the potentially serious side effects, it’s important to consult with doctors who understand this disease and this drug.”

A Valuable Drug for a Debilitating Condition

TGCT, also called pigmented villonodular synovitis (PVNS), is not considered a cancer because it doesn’t spread to other parts of the body. But it is a condition that can be painful and debilitating. It most often affects the knees. The disease is most often treated with surgery. If it continues to come back, people with the condition may run out of treatment options.Tenosynovial giant cell tumor (TGCT) is also called pigmented villonodular synovitis (PVNS).

In the phase III study, which enrolled patients in the United States, Europe, and Australia, 120 people were randomized to receive either the drug or a placebo. After nearly six months, 39% of people who got the drug had a measurable response, meaning that their tumors got smaller. Many of those who responded to the drug had noticeable improvements in range of motion and a reduction in pain in the affected joint. No one who received a placebo had any measurable response.

The drug is a targeted therapy that works by blocking a protein called colony-stimulating factor 1 kinase. This protein drives the development and growth of these tumors.

Pexidartinib is approved for people who can no longer have surgery for their tumor, or who are trying to avoid amputation. Because the drug can cause liver damage, the FDA did not approve pexidartinib for people who can be treated surgically or if the tumor is not seriously affecting a person’s quality of life.For the right patient, this is a drug that can really help.William D. TapMedical oncologist

“Unfortunately, this drug can cause a specific type of liver toxicity called cholestatic hepatotoxicity,” Dr. Tap explains. “It’s exceedingly rare, but when it occurs, it can be very dangerous. It’s important that people who get the drug are treated somewhere where they can be closely monitored for liver problems.” He explains that for this reason, only certain pharmacies will be able to dispense the drug, and doctors will have to go through a certification process before they can prescribe it.Back to top 

Meaningful Improvements for a Neglected Condition

Despite the warnings, Dr. Tap says the approval of pexidartinib is an important breakthrough that can lead to meaningful improvements in many people’s lives.

“TGCT has been neglected by much of the medical community and the pharmaceutical industry for a long period of time,” he notes. “Even though it’s rare, it has a relatively high prevalence. This is because it tends to first affect people when they are in their 20s and 30s. If it can’t be successfully treated with surgery, they have to live with it for the rest of their lives. So there are a lot of people out there who are coping with this disease.”

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Researchers Identify a Bacterial Species That Could Protect against Hospital-Acquired Infections

Source: Memorial Sloan Kettering - On Cancer
Date: 08/21/2019
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Hospital-acquired infections are a major threat, especially for people whose immune systems may be compromised because of cancer treatment. In recent years, researchers have been studying fecal microbiota transplants as a way to treat this serious complication. These transplants involve collecting stool from a healthy donor and delivering it into the intestine of the patient. The beneficial microorganisms from the transplant restore the balance of healthy bacteria in the gut.

Little is known, however, about which species of bacteria offer protection against harmful pathogens or exactly how they provide this benefit. A new study from Memorial Sloan Kettering is reporting the first evidence of a bacterial species that appears to maintain the balance of healthy microbes by killing dangerous ones. The findings also suggest how it mounts this attack. The research was reported August 21 in Nature.

“A lot of work is being done to figure out how harmful pathogens are able to colonize the human body,” says first author Sohn Kim, an MD-PhD student in the Tri-Institutional MD-PhD Program of MSK, Weill Cornell Medicine, and The Rockefeller University. “This project provides important new information about the bacteria that keep them in check.”

Focus on a Deadly Infection

The study focused on a particularly threatening hospital-acquired infection called vancomycin-resistant Enterococcus (VRE). VRE sickens about 20,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and kills up to 10% of them. Earlier work led by former MSK graduate student Silvia Caballero, a co-author on the current study, showed that a mixture of four bacterial strains protect lab mice from VRE. These strains are normally found in the gastrointestinal tracts of healthy people.

The new study built on this earlier work by conducting a series of experiments to isolate one of these four bacterial strains: Blautia producta. “The next step was to determine the mechanism by which Blautia producta mediates protection against VRE,” Dr. Kim says. It turned out that a protein produced by Blautia producta is able to kill VRE even when the bacterial cells themselves aren’t present. Further study revealed that this protein is a lantibiotic, a type of antibiotic that is manufactured by microorganisms.

“If you think of Blautia producta as a member of the microbiota that helps maintain order within the gut, this lantibiotic is what it uses to do that,” says MSK infectious diseases expert Ying Taur, a co-author on the study. “This study really helps further our understanding of how all this works and provides important new insight.”

Evaluating the Effects of a Bacterial Product

The researchers did a number of additional studies. These included sequencing the gene that codes for the lantibiotic and performing RNA sequencing to determine when the gene is expressed.

They also tested the lantibiotic against about 150 strains of intestinal bacteria, to gain a sense of its spectrum of activity. This part of the research was significant because a major side effect of the antibiotics that doctors prescribe is that they can wipe out these healthy strains.

The team found that Blautia producta and the lantibiotic did not damage healthy strains. In fact, when they reviewed their library of samples collected from healthy donors, the researchers learned that about half of them already had Blautia producta and this lantibiotic product.

“It’s remarkable how precise this product is at targeting harmful microbes while sparing healthy ones,” Dr. Taur notes. “This is something we do not know how to do with any antibiotics that we have now. Our antibiotics are very clunky in comparison to the precision of what these bacteria do.”

Moving Forward with More Research

More work is needed before this approach can be tested in people with VRE infections. Drs. Kim and Taur say they haven’t even determined how a treatment would be best administered or whether they would use Blautia producta or the isolated lantibiotic. The treatment could possibly be given as a pill, or the findings from this study could be used to develop a more specialized type of fecal microbiota transplant. They plan to study various approaches in mouse models.

“Previously, studies have shown that Blautia is associated with better outcomes in people who have developed graft-versus-host disease (GVHD) after having a bone marrow transplant with donor cells,” says study co-author Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “In addition, we have recently found that Enterococcus is associated with increased incidence of GVHD. These findings offer exciting opportunities to control GVHD and improve outcomes for people having transplants.”

“There are a lot of things we still don’t know, but we have learned so much from this study,” Dr. Taur concludes. “It was really an amazing piece of detective work.”

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8 Questions with Valerie Rusch: Lung Cancer Surgeon Reflects on Advances and Providing Excellent Care

Valerie Rusch is Vice Chair for Clinical Research in the Department of Surgery at MSK. She is a thoracic surgeon who treats lung cancer and esophageal cancer, malignant pleural mesothelioma, and other tumors of the chest. She was the first woman named as a service chief and promoted to full Member in her department at MSK.

1. In October, you will become president of the American College of Surgeons. What does that entail?

The group is the world’s largest surgical organization. It represents 80,000 surgeons across all specialties, both nationally and internationally. Its mission is to improve care by setting high standards for surgical practice and education. I will be the college’s 100th president but only the fourth woman to hold the position. My role is to represent the organization at educational conferences around the world.

2. Did you always know you wanted to be a doctor?

My father was in the Navy Medical Corps during World War II and later became an otolaryngologist. This gave me some exposure to the medical world. In college, I worked as an operating room technician for two summers. My father’s family was Swiss, and a bilingual education was important, so I attended the Lycée Français in New York City. I considered multiple career paths, including being an interpreter, but ultimately was most attracted to medicine. I ended up going to medical school at the College of Physicians and Surgeons at Columbia University.

3. How do you cope with being a woman in a male-dominated field?

There have been challenges. But my father always said, “No one can argue with excellence.” Although I’ve certainly encountered instances of prejudice, I’ve focused on delivering excellent clinical care, helping my patients, and taking advantage of research opportunities to develop new treatments. It has been rewarding to see substantially more women in surgery and to see them increasingly accepted within the surgical community.

4. How did you get interested in thoracic surgery?

During my residency in general surgery at the University of Washington, I was exposed to many surgical subspecialties. I found that thoracic surgery provided a blend of technically challenging procedures and cognitive decision-making. I particularly appreciated the meaningful long-term relationships that develop during the care of people with cancer.

5. When did you come to MSK?

In 1989, I was recruited to travel to New York City and interview for a position at MSK. It came at the perfect time because I had recently decided to focus my career on cancer care. Thoracic surgeons do a lot of different things, including lung transplants, reconstruction after trauma, and treatment of benign diseases. Cancer was where I felt I could make the biggest difference.

6. How has treatment for lung cancer changed over time?

Minimally invasive surgical techniques have made recovery easier, and we can operate more safely on older patients due to advances in pre- and postoperative care. New radiotherapy techniques can help patients who cannot have surgery. Lung cancer screening with CT imaging has led to many more people being diagnosed with very early-stage tumors, when they may be cured by surgery or radiation therapy alone. And targeted therapies and immunotherapies have led to higher survival rates in people with more advanced lung cancers.

7. What is a challenge that remains?

One emotional challenge is the guilt that patients feel because the majority of these cancers are linked to smoking. They tend to hold themselves responsible for their disease. Also, smoking rates have declined in North America but remain high in many parts of the world.

8. How does MSK support people with lung cancer?

We have many medical and psychosocial resources for patients throughout their treatment and afterward. Now that many of our patients are living longer, survivorship care has become important. Subsequent primary lung cancer after successful treatment of an initial lung cancer is a significant risk. We developed the first lung cancer survivorship program nationally to provide lifelong follow-up, supportive care, and screening. It has become a significant part of our care.